Oxidized low-density lipoproteins induce rapid platelet activation and shape change through tyrosine kinase and Rho kinase–signaling pathways

Wraith, Katie S.; Magwenzi, Simbarashe; Aburima, Ahmed; Wen, Yichuan; Leake, David; Naseem, Khalid

Abstract

Oxidized low-density lipoproteins (oxLDL) generated in the hyperlipidemic state may contribute to unregulated platelet activation during thrombosis. Although the ability of oxLDL to activate platelets is established, the underlying signaling mechanisms remain obscure. We show that oxLDL stimulate platelet activation through phosphorylation of the regulatory light chains of the contractile protein myosin IIa (MLC). oxLDL, but not native LDL, induced shape change, spreading, and phosphorylation of MLC (serine 19) through a pathway that was ablated under conditions that blocked CD36 ligation or inhibited Src kinases, suggesting a tyrosine kinase–dependent mechanism. Consistent with this, oxLDL induced tyrosine phosphorylation of a number of proteins including Syk and phospholipase C γ2. Inhibition of Syk, Ca2+ mobilization, and MLC kinase (MLCK) only partially inhibited MLC phosphorylation, suggesting the presence of a second pathway. oxLDL activated RhoA and RhoA kinase (ROCK) to induce inhibitory phosphorylation of MLC phosphatase (MLCP). Moreover, inhibition of Src kinases prevented the activation of RhoA and ROCK, indicating that oxLDL regulates contractile signaling through a tyrosine kinase–dependent pathway that induces MLC phosphorylation through the dual activation of MLCK and inhibition of MLCP. These data reveal new signaling events downstream of CD36 that are critical in promoting platelet aggregation by oxLDL.

Citation

Wraith, K. S., Magwenzi, S., Aburima, A., Wen, Y., Leake, D., & Naseem, K. (2013). Oxidized low-density lipoproteins induce rapid platelet activation and shape change through tyrosine kinase and Rho kinase–signaling pathways. Blood, 122(4), 580-589. https://doi.org/10.1182/blood-2013-04-491688

• Journal Article Type: Article
• Acceptance Date: May 14, 2013
• Online Publication Date: May 22, 2013
• Publication Date: Jul 25, 2013
• Deposit Date: Jan 5, 2024
• Journal: Blood
• Print ISSN: 0006-4971
• Electronic ISSN: 1528-0020
• Publisher: American Society of Hematology
• Peer Reviewed: Peer Reviewed
• Volume: 122
• Issue: 4
• Pages: 580-589
• DOI: https://doi.org/10.1182/blood-2013-04-491688
• Public URL: https://hull-repository.worktribe.com/output/4362166